Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
Biochemistry. 2010 Apr 6;49(13):2843-50. doi: 10.1021/bi1000678.
Glutamate receptors are important potential drug targets for cognitive enhancement and the treatment of schizophrenia in part because they are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system. One approach to the application of therapeutic agents to the AMPA subtype of glutamate receptors is the use of allosteric modulators, which promote dimerization by binding to a dimer interface thereby reducing the degree of desensitization and deactivation. AMPA receptors exist in two alternatively spliced variants (flip and flop) that differ in desensitization and receptor activation profiles. Most of the structural information about modulators of the AMPA receptor targets the flip subtype. We report here the crystal structure of the flop-selective allosteric modulator, PEPA, bound to the binding domains of the GluA2 and GluA3 flop isoforms of AMPA receptors. Specific hydrogen bonding patterns can explain the preference for the flop isoform. This includes a bidentate hydrogen bonding pattern between PEPA and N754 of the flop isoforms of GluA2 and GluA3 (the corresponding position in the flip isoform is S754). Comparison with other allosteric modulators provides a framework for the development of new allosteric modulators with preferences for either the flip or flop isoforms. In addition to interactions with N/S754, specific interactions of the sulfonamide with conserved residues in the binding site are characteristics of a number of allosteric modulators. These, in combination with variable interactions with five subsites on the binding surface, lead to different stoichiometries, orientations within the binding pockets, and functional outcomes.
谷氨酸受体是认知增强和精神分裂症治疗的重要潜在药物靶点，部分原因是它们是脊椎动物中枢神经系统中最普遍的兴奋性神经递质受体。一种将治疗剂应用于 AMPA 型谷氨酸受体的方法是使用变构调节剂，它通过与二聚体界面结合来促进二聚体形成，从而降低脱敏和失活的程度。AMPA 受体有两种交替剪接的变体（翻转和翻转），它们在脱敏和受体激活谱上有所不同。关于 AMPA 受体靶标调节剂的大部分结构信息都针对翻转亚型。我们在这里报告了 flop 选择性变构调节剂 PEPA 与 AMPA 受体的 GluA2 和 GluA3 flop 同工型的结合域结合的晶体结构。特定的氢键模式可以解释对 flop 同工型的偏好。这包括与 flop 同工型的 GluA2 和 GluA3 的 N754 之间的双齿氢键模式（flip 同工型的对应位置是 S754）。与其他变构调节剂的比较为开发对翻转或翻转同工型具有偏好的新型变构调节剂提供了框架。除了与 N/S754 的相互作用外，磺酰胺与结合位点保守残基的特定相互作用是许多变构调节剂的特征。这些与结合表面上五个亚位点的可变相互作用相结合，导致不同的化学计量、结合口袋内的取向以及不同的功能结果。
